21-aldo steroids



United States Patent-O ZI-ALDO STEROIDS Josef Fried, New Brunswick, N. J., assignor to 01in Mathieson Chemical Corporation, New York, N. Y., a corporation of Virginia No Drawing. Application November 12, 1954 Serial No. 468,575

15 Claims. (Cl. 260-23955) This invention relates to the synthesis of valuable steroids.

One of the objects of this invention is the provision of an advantageous process of preparing steroids of the l7-unsubstituted pregnane (including the pregnene and allopregnane) series having a 21-a1do or acetalized aldo group, a 9a-ha1o group, and an llfi-hydroxy or ll-keto group.

Anotherobject of this invention is the provision .of certain compounds useful either for their own physiological action or as intermediates in the preparation of physiologically-active derivatives. i

The compounds of this invention comprise steroids of the pregnane including the pregnene and allopregnane) series unsubstituted in the 17-position and having a 21- aldo or acetalized aldo substituent, a 9a-halo substituent, and an llg-hydroxy or ll-keto substituent. These new steroids are prepared by the process of this invention, which essentially comprises converting a 9a-halo, 11 8- hydroxy or ll-keto, 17v z-hydroxy, 21-hydroxy or acyloxy steroid of the pregnane (including the pregnene and allopregnane) series to the corresponding 9m-halo, 11,8- hydroxy or ll-keto, 17-unsubstituted, 21-acetalized aldo derivative, by treatment of the former with an alcohol under anhydrous acidic conditions. The 21-aceta1 derivative thus formed may then be converted to the corresponding free 21-aldehyde by treatment of the acetal with a mineral acid in an aqueous organic solvent in which the acetal is soluble (e. g. acetic acid or dioxane and water).

Among the compounds of this invention which have an acetalized 21-a1do group are those of the general formula:

keto group, X is an a-halogen group and is either of}? the acetalized aldo groups wherein B is a saturated aliphatic radical, such as an alkyl (e. g. a lower alkyl, such as methyl, ethyl, propyl,

n-butyl or amyl), a haloalkyl (e. g. a halo-substituted lower alkyl such as chloromethyl, Z-fluoroethyl, 2-bromopropyl, or '1,2-dichloroethyl), or an alkoxyalkyl (e. g. a lower alkoxyalkyl, such as ethoxymethyl, methoxyethyl, or ethoxyethyl); or B is an aralkyl radical such as a phenylalkyl (e. g. benzyl, phenethyl, tolylethyl, p-chlorobenzyl, or anisylmethyl), or a naphthylalkyl (e. g. naphthylmethyl); and B is a saturated aliphatic divalent radical such as an alkylene (e. g. a lower alkylene, such as ethylene, propylene, Z-methylpropylene, or butylene), a haloalkylene (e. g. a halo-substituted lower alkylene, such as chlorethylene, fluoropropylene, or 1-ch1oro-2- ethylpropylene), or an alkoxyalkylene (e. g. a lower alkoxy-lower-alkylene,'such as ethoxyethylene, 2-methoxypropylene, or methoxyethylene).

Representative acetalized 21-aldo steroids of this invention include the acetals (both straight chain and cyclic) of:

9a-fluoro-A -pregnene-11p-ol-3,20-dione-21-a1 [e. g. 901- fiuoro-M-pregnene-l lB-ol-3,20-dione-2 l-al dimethyl acetal, the corresponding 21-diethyl acetal, the corresponding 21-di-npropyl acetal, the corresponding 21-di-n-butyl acetal, the corresponding ZI-dibenzyl acetal, and the corresponding 21-alkylene (i. eethylene) cyclic acetal]-;

9a-chloro-A -pregnene-11/3-ol-3,2O-dione-2l-a1 [e. g.

9u-chloro-A -pregnene-11fl-ol-3,20-dione 21 a1 dimethyl acetal, the corresponding 21-diethyl acetal, the corresponding 2l-di-n-propyl acetal, the corresponding 21-di-nbutyl acetal, the corresponding 2l-dibenzyl acetal, and

tall;

-9a fluoro-A -pregnene-3,11,20-trioner21-al [e. g. 9ozfluor0-A '-pregnene-3,l1,20-trione-21-a1 dimethyl acetal, the corresponding 21-diethyl acetal, the corresponding 2l-di-n-propyl acetal, the corresponding 21-di-n-butyl ac-' etal,-.the corresponding 21-dibenzyl acetal, and the corresponding 2l-alkylene (i. e. ethylene) cyclic acetal];

9a-chloro-A pregnene-3,11,20-trione-2l-al [e. g. 9achloro-A*-'pregnene-3,11,20-trione-21-al dimethyl acetal, the corresponding Zl-diethyl acetal, the corresponding 21-di-n-propyl acetal, the corresponding 21-di-n-butyl acetal, the corresponding 21-dibenzyl acetal and the corresponding 21-ethylene acetal];

'9u bromo-A*-pregnene-3,1-1,ZO-trione-Zl-al IIe. g.'9vzbromo-A -pregnene- 3,l1,20-trione-21-al dimethyl acetal, and its ZI-diethyl, 21-di-n-propyl, ZI-di-n-butyl, 2l-dibenzyl and 2l-ethylene derivatives]; and

9cz-iodo-A -pregnene-3J1,20-trione-21-al [e. g. 9cc-i0d0- A -pregnene-3,1 1,20-trione-21-al-dimethyl acetal] Among the compounds of this invention which have a 21-aldo group are those of the general formula:

wherein the 4,5 position is double bonded or saturated (preferably double bonded), and wherein R, R, R, R'", and X are as above-defined. Since in the presence of a hydroxy-containing solvent (e. g. water), the 2l-aldo group'readily'adds a mole of the solvent and, therefore, exists as a hydrate (or equivalent), the terms 21-aldo and 21-aldehyde are hereby defined asincluding such derivatives as the hydrate, but not the acetal derivatives, which are referred to as acetalized aldo or aldehydes.

Representative 2l-aldo steroids of this invention include: 9a-fiuoro-A -pregnene-1 1,6-ol3,20-dione-21-al; 9ozchlbro-M-pregnene-l 1-,6-ol-3,20-dione-21-al 'Qa-brom o-A pregnene 11 8- ol-3,20-dione-21-al; 9a-iodo-A -pregnene- 1-1-B-ol-3,20-dione-2l-al; 9a-fluoro-A -pregnene-3J 1,20-trione-2l-al; 9ot-chloro-A -pregnene-3,11,20-trione-2l-al; 9abromo A -pregnene-ll1,20-trione-2l-al; and 9ot-iodo-A pregnene-3,1 1,20-trione-21-al.

Among the compounds which are useful as starting materials in the practice of this invention are those of the general formula CHaOZ (preferably double-bonded), and wherein R, R, R", R', and X are as above-defined, and Z is hydrogen or an acyl radical, such as: an aliphatic acyl radical, as exemplified cortisoneacetate, 9u-iodohydrocortisone, and 9u-iodohye drocortisone acetate, and the 9 ahalocortisones and the esters (preferably lower alkanoic acid esters) thereof, e. g. 9u-fluorocortisone, 9u-fluorocortisone acetate, 9%

chloro-cortisone, 9u-chlorocortisone acetate, 9m-bromocortisone, 9a-bromocortisone acetate, 9a-iodocortisone, and 9u-iodocortisone acetate.

According to the process of this invention, these starting materials are. reacted under anhydrous conditions'in an acidic medium with either a monohydric alcohol" of the formula BOH or a dihydric alcohol of the formula B(OH) wherein B and B are as above-defined, preferably with an alcohol of the formula BOH, wherein B- is a lower alkyl (e. g., methyl, ethyl, n-propyl, or nbutyl) or benzyl radical. The reactionis preferably carried out by dissolving the starting material in an anhydrous organic solvent, such as chloroform, and treating the solution with a mineral acid such as hydrogen chloride or a strong organic acid, such as trichloro acetic acid or.

The acetalderivative formed. by theiflrst step of the process of this invention may then be converted to the by an alkanoyl radical (e. g. lower alkanoyl, such as acetyl, propionyl, or butyryl), a halo-substituted alkanoyl, a intro-substituted alkanoyl, an alkoxy-substituted alkanoyl, or an amino-substitued alkanoyl; an aralkanoyl, such as a phenyl-alkanoyl radical (e. g. phenylacetyl); or an aroyl, such as a phenyl carbonyl (e. g. benzoyl, toluyl, or cumoyl). The preferred compounds of this group are those wherein the 4,5 position is doublebonded, R and R together represent oxo, R" is hydrogen, R is ,B-hydroxy, or together R" and R is oxo, and Z is hydrogen or lower alkanoyl (e. g., acetyl). 7

Representative of the compounds utilizable in the process of this invention are: the 9a-halohydrocortisones and the esters (preferably lower alkanoic acid esters) thereof, e. g. 9a-fluorohydrocortisone, 9u-fluorohydrocortisone acetate, 9a-chlorohydrocortisone, 9oi-chloro-hydrocortisone acetate, 9a,-bromohydrocortisone, 9u-bromohydro- CHQOCCCHI corresponding free aldehyde by reacting the acetal with an aqueous mineral acid, .suchv as hydrochloric acid or perchloric acid, in mixture with an organic solvent, such 1 V as acetic acid, dioxane, acetone, etc., preferably at room wherein the 4,5 position is double-bonded or saturated temperature. g

, A modification of the process of this invention consists of the direct oxidation of an aeetal derivative of a '21- aldo' steroid having an llp-hydroxy group to the corre sponding, acetal derivative havingv an ll-keto group. Thus, to form a-Zl-aldo steroid having an ll-keto group, instead of starting with the corresponding steroid having an ll-keto group and converting this ll-keto steroid to acetal derivative: and thence to the free aldehyde, the

llfi-hydroxy derivative (R" is hydrogen, R is fi-hydroxy) is chosen as the initial reactant, and this reactant is converted to the 21-acetal derivative. The acetal derivative is then reacted with a customary oxidizing agent, such as, chromic oxide in an acidic medium, to oxidize the llfl-hydroxy group to keto, and the ll-keto 21-- Both the acetal derivatives and free aldehydes of this invention are active materials which possess glucocorticoid as well as mineralocorticoid activity. Thus, the new steroids of this invention can be administered instead of, an'd in the same manner as, cortisone or hydrocortisone in the treatment of rheumatoid arthritis and dermatomyositis, and desoxycorticosterone in the treatment of Addisons disease or adrenal insufiiciencies. The dosage for such administration is of course dependent on the relative activity;'thus, where the acetal derivative, for example, has activityof the same order as hydrocortisone, for example, the dosage is of the same order.

The following examples are illustrative of the invention (all temperatures being in centigrade):

EXAMPLE 1 9a fluoro -A pregnene-IJ5-0l-3,20-didne 21 -al-dimethyl acetal (III) from Qd-fluorahydrocortisone acetate (I) A solution of 505 mg. of 9u-fluorohydrocortisone acetate in 13 ml. of chloroform, 32 ml. of anhydrous methanol and 7 m1. of 1.5 N anhydrous methanolic hydrogen chloride is allowed to stand at room temperature for 64 hours. Sodium bicarbonate solution is then added until the mixture is basic and after addition of 25 ml. of chloroform the layers are separated. The aqueous layer is extracted again with chloroform and the combined chloroform extracts Washed with water. After drying with sodium sulfate the chloroform is removed in vacuo and the residue crystallized from ethyl acetate. After an additional recrystallization from ethyl acetate the pure compound melts at about 174-175 M1 +184 (c., 0.7 in CHCl xii-L 283 mp. (e=l4,600); mg 2.91,; (OH), 5.80 keto), 5.97 6.16;, (13 -3 ketone) 'A-naly.s'z'.s'.Calcd. for C H O F: C, 67.26; H, 8.14; OCH 15.20. Found: C, 67.56; H, 8.00; OCI-I 14.53.

9a-fluoro-A -pregnene-11B-ol-3,20-dione 21-al-dimethyl acetal is as active as cortisone acetate in the rat liver glycogen assay and about equal to desoxycorticosterone in maintaining the life of adrenalectomized rats and in retaining sodium.

By substituting 32 ml. of anhydrous ethanol for the methanol and 7 ml. of 1.5 N anhydrous ethanolic hydrogen chloride for the methanolic hydrogen chloride in Example 1, 9a-fluoro-A -pregnene-l15-ol-3,20-dione-21- al-diethyl acetal is produced. Similarly, by substituting other alkanols for methanol in Example 1, the corresponding 21-dialkyl acetal derivatives are formed. Thus, n-propanol yields 90: fluoro A pregnene l1fl-ol-3,20 dione-ZI-aI-di-n-propyl acetal an'd n-butanol yields 90:-

fluoro-A -pregnene-11fl-ol-3,20-dione-2l-al-di-n-butyl acetal, while ethylene glycol yields 9ac-fluoro-A randrostene 1lfi-ol-3,20-dione-2l-al-ethylene acetal.

EXAMPLE '2 9oz fluoro A -pregnene-11j3-0l-3,Z0-dione 21 ail-dibenzyl acetal (IV) from 9afluorohydr0cortis0rte acetate (I) A solution of 500 mg. of 9a-fluorohydrocortisone acetate in 25 ml. of 0.46 N hydrogenchloride in chloroform and 5 ml. of benzyl alcohol is allowed to remain at room temperature for 64 hours with the exclusion of moisture. The resulting mixture is worked-up as describedin Example 1 furnishing 9a-fiuoro-A -pregnene-11B-ol-3,20- dion'e 21-al-dibenzyl acetal.

EXAMPLE 3 9a fluoro A pregnene-]1fi01-3,20-dione 21 -al-hydrate (VI) from 9a-fluoro-M-pregnene-llp-ol-3,20-di0ne-.21- al-dz'methyl acetal (III) 7 A solution of mg. of 9B-fiuoro-A -pregnene-1lfi-ol 3,20-dione ZI-al-dimethyl acetal in 2 ml. of glacial acetic acid and 2 ml. of 2 N aqueous hydrochloric acid is allowed to stand at room temperature for 4 days. An aqueous solution of 400 mg. of sodium bicarbonate is added and the mixture extracted with chloroform. The chloroform solution is in turn extracted with bicarbonate solution and with water and dried over sodium sulfate.

EXAMPLE 4 9a-fluoro-A -pregnene-3,11,ZO-trione 21 -al-dim ethyl acetal (IX) from 9a-flu0r0-A -pregnene-11B-ol-3,20-di0ne'21- al-dimethyl acetal (III) To a solution of 100 mg. of 9a-fluoro-Af-pregnene-11B- ol-3,20-dione 21-al-dimethyl acetal in 4 ml. of glacial acetic acid is added a solution of 25 mg. ofCrO in 2.5 ml. glacial acetic acid. After-ZO-minutes 1 1111.;of' alco- '7 hol is added an'd the mixture concentrated to a sirup. Water and chlorofrom are added and after separation of the layers, the chloroform phase is extracted with water, bicarbonate solution, and again with Water. The chloroform extract is dried over sodium sulfate and evaporated to dryness in vacuo. The residue represents 9a-fluoro- A -pregnene-3,11,20-trione 2l-al-dimethyl acetal. Its 'biological activity is approximately equal to that of the corresponding llp-hydroxy compound.

9u-fluoro-A -pregnene-3,11,20-trione 21 -al dimethy acetal can also be prepared directly from 9a-fiuorocortisone acetate (V111) by substituting 9oc-fluorocortisone acetate for 9a-fluorohydrocortisone acetate in the process of Example 1. Similarly other 9u-fluoro-A -pregnenel1 3ol-3,20-dione Zl-al-acetals such as the 2l-diethyl acetal, the 21-di-n-butyl acetal, the 21-di-n-propyl acetal, the 2l-dibenzyl acetal and the 21-ethylene acetal can be oxidized to the corresponding ll-keto 21-acetal derivatives by the process of Example 4.

The 9a-fluoro, 21-acetals, e. g., 9a-fluoro-A -pregnene- 3 l-1,20-trio'ne Zl-aI-dimethyl acetal (IX), can then be converted to the corresponding 9u-fluoro-21-aldehyde hydrates, e. g. 9u-fiuoro-A -pregnene-3J1,2O-trione 21- al-hydrate (XI), by the method of Example 3.

EXAMPLE 5 A solution of 1 g. of 9u-chlorohydrocortisone acetate in 26 ml. of chloroform, 64 ml. of anhydrous methanol and 14 ml. of 1.5 N methanolic hydrogen chloride is allowed to stand at room temperature for 64 hours. The mixture is worked up as described in Example 1 for the corresponding fluoro compond. Evaporation of the chloroform extract in vacuo furnishes a residue (about 1.06 g.) which crystallizes readily from methanol. About 730 mg. of crystalline product of M. P. about 106-109 is obtained. This material contains 1 mole of methanol of crystallization. The anhydrous compound is obtained by recrystallization from ethyl acetate-hexane, M. P. about 138'; [(11 +191 (c., 0.93 in chloroform);

Nuiul Mm;

Analysz'a-Calcd. for C H O Cl: C, 65.00; H, 7.82;

Cl, 8.34; OCH 14.59. Found: C, 65.29; H, 7.73; Cl, 8.46; OCH 14.79. 9a-chloro-A -pregnene-115-01- 3,20 dione 21 a1 dimethyl acetal is about /3 as active as cortisone acetate in the rat livergycogen assay, and about twice as active as desoxycorticosterone in sodium retention in the adrenalectomized rat.

By substituting other alcohols such as ethanol, n-propanol, n-butanol, beuzyl alcohol, and ethylene glycol for the methanol in Example 5, the corresponding 21-diethyl acetal, 21-di-n-propyl acetal, 21-di-n-buty1 acetal, 21-di- 'benzyl acetal, and ethylene acetal derivatives of 90:- chloro-A -pregnene-l1B-ol-3,20-dione 21-al are obtained.

EXAMPLE 6 9u-chloro-A -pregnene-l1 3-ol-3,20-dione 21 al hydrate (VII) from 9a-chloro-A -pregnene-l 1 ,8-0l-3,20-dione 21 -al-dimethyl acetal (V) A solution of 100mg. of 9a-chloro-A -pregnene-1lfi- .The chloroform solution is in turn extracted with bicarbonate solution and with water and dried over sodium sulfate. Evaporation of the chloroform extract in vacuo leaves a residue consisting of 9a-chloro-A -pregnene-llflol-3,20-dione 21-al-hydrate.

Similarly the corresponding ZI-diethyl acetal, 21-di-npropyl-acetal, 21-di-n-butyl acetal, 21-dibenzyl acetal and: 21-ethylene acetal derivatives can be converted to the 21-aldehyde hydrate by the method of Example 6.

The 21-dimethyl acetal (V) of Example 5, as well as its 'diethyl, di-n-propyl, di-n-butyl, d'ibenzyl and ethylene analogues, can be converted to the corresponding 11- "keto derivative e. g., 9a-chloro-A -pregnene-3,1 1,20- trione 2l'-al-dimethyl acetal (X), by the method of Example 4, which in turn can be converted to 9a-chloro-A pregnene-3-,11,20-'trione 21-al-hydrate (XII) by the method of Example 3.

If 9a-bromo hydrocortisone acetate, 9a-iodo hydrocortisone acetate, 9a-bromo cortisone, or 9a-i0d0 cortisone is substituted for the fluoro or chloro derivatives in Examples 16, the corresponding brorno and iodo steroids 21-al-21-dibenzyl acetal, the 9a-halo-A pregnene-llflol- 3,20-dione 21-al-dibenzyl acetals, produced from 9u-halohydrocortisone (or an ester thereof) by the method of Example 2, are catalytically reduced by means of a palladium catalyst to the corresponding 9u-halo-corticosterone. I

EXAMPLE 7 9a-fluorocortic0sterone acetate from 9a-fluoro-A -pregnene-l1fi-0l-3,20-dione-21-al-dibenzyl acetal (IV) A mixture of l g. of '9bt-fluoro-A -pregnene-llfl-ol- 3,20-dione-21-al-dibenzyl acetal, 50 mg. of p-toluenesulfonic acid and 20 ml. of 2-methyl-2 ethyldioxo1an'e is heated and the liberated butanone together with the reactant dioxolane distilled slowly through a small Claisen-Vigreux column at atmospheric pressure for a period of 5 hours (ca. 8 ml. of distillate). The cooled reaction mixture is diluted with benzene and the resulting solution extracted with dilute sodium bicarbonate and water. The benzene solution is dried over sodium sulfate and the solvents removed in vacuo. The residual 3 dioxolane of 9a-fiuoro-A -pregnene-llB-ol-3,20dione-21 al-dibenzyl-acetal is crystallized from acetone-hexane and dissolved in 50 ml. of ethyl acetate for the subsequent reduction. To the resulting solution is added 200 ingot 5% palladium on charcoal and the suspension shaken the presence of hydrogen until the absorption of hydro; gen comes to a standstill. The solution is filtered and the solvent evaporated in vacuo. The resultant residue is treated with 10 ml. of acetic acid at for 30 minutes to hydrolyze the 3-dioxolane grouping. The hydrolysis solution is concentrated to small volume in vacuo, extracted with chloroform andthechloroform solution washed with bicarbonate and with water. The chloroform extract is dried over sodium sulfate and evaporated to dryness in vacuo. The resulting 9wfluoro corticosterone is acetylated with 2 ml. of pyridine and 2 ml. of acetic anhydride for 12 hours and the acetylat-.

ing agents removed in high vacuum. The resulting residue is crystallized from ethyl acetate and after several recrystallizations fromthe same solvent affords pure 9afluorocorticosterone acetate, M. P. 212-213";

Although the 9a-bromo and 9a-i0d0 21-aldo steroids of this invention, can be prepared by the methods of Ex- :9 amples 1 through 6, in some instances it may be preferable to form these halide derivatives indirecfly from the corresponding 9a-Chl0l'0 ZI-acetal derivatives by way of the 918,115-oxido intermediates. Thus, the 9cz-Ohl0l'0 2l-acetal derivatives are reacted with a salt of a strong base and a weak acid, such as an alkali metal carbonate or bicarbonate (i. e. potassium bicarbonate) or an alkali metal lower alkanoate (i. e. potassium acetate), and the 9p,1'1p-oxido compound, thus formed, is then reacted with a hydrogen halide (e. g. hydrofluoric acid, hydrochloride acid, hydrobromic acid or hydroiodic acid) to form the 9a-halo 11phydroxy 21-aldo acetal derivative. This series of steps can be represented by the following schematic analysis and examples:

EXAMPLE 8 9 8, 11flmxido-M-pregnene-3,20-di0ne 21 -al-dimethyl dcetal (XIII) from 9a-chl0ro-A -pregnene-11,3-l-3,20-di0ne 21 -al-dimethyl acetal (V) To a solution of 130 mg. of 9a-chloro-A -pregnene-llflol-3,20-dione 2l-al-dimethyl acetal in 10 ml. of methanol is added a solution of 105 mg. of potassium carbonate in 0.5 ml. of water. The resulting suspension is placed into a mechanical shaker at room temperature for 3 hours, after which time 4 ml. of water is added, and the solution is freed from methanol in vacuo. Chloroform is added to the residue, and after mixing and separation of the EXAMPLE 9 9a chIoro A pregnene 3,20 dione 21 al dimethyl acetal (V) from 919,113 oxido A pregnene- 3,20-di0ne-21-al-dimethyl acetal (XIII) To a solution of 100 mg. of 9B,l1p-oxido-A -pregnene- 3,20-dione-2l-al-dimethyl acetal in 10 ml. of chloroform is added at 0 C;. 1.5 of 0.5 N hydrochl oric acid in chloroform. After 30 minutes, ice and dilute bicarbonate are added to wash out excess acid; and after separation of the layers, the chloroform solution is washed with water,

5 dried over sodium sulfate and evaporated to dryness in vacuo. The residue is crystallized from methanol to give a crystalline product containing one mole of methanol of crystallization. The anhydrous compound is obtained by recrystallization from ethyl acetate-hexane and is 10 identical with the compound-formedin Example 5, -a proven byv mixed melting point and opticaLrotation data.

EXAMPLE 10 iv v 9a bramo A pregnene 3,20 dione 21 '-f z'z'I dimeithyl To a solution of 25 mg. of 9fl,ll;3-oxido- A s-pr'e gnenedroiodic acid for hydrobromic acid in Example 10, the corresponding Qa-iodo compound (XV) is formed. 1-.

The QaDI'OmOOI. 9a-i0d0 ZI-acetal derivatives can be converted to the corresponding 2l-aldehyde by the method of Example 3, or can be oxidized to the 9a-bromo or 90:- iodo ll-keto 2l-acetal derivative by the method of Example 4. I

These 9abromo and 9az-i0d0 2l-aldo steroids, aside from their activity as glucocorticoids and mineralocorticoids, have an added utility as intermediates in the preparation of the known 9a-dehalo analogues. Thus, the 9mbromo and 9u-i0d0 steroids may be reduced by treatment with usual reducing agents, such as zinc in glacial acetic acid, to remove the 9a-halo radical and form the 9-unsub stituted derivatives. 1 j. The invention may be variously otherwiseembodied within the scope of the appended claims.

I claim: w r

l. A steroid selected from the groupconsisting of those of the formula wherein individually R is hydrogen, R is hydroxy and together R and R is keto, individually R" is hydrogen, R"

is p-hydroxy and together R and R" is keto; X is an abeware wha einea' is; a rseieai at the class 'eo'nsist'irig of lower alky'l, halo-sfibstifutd ldwer alkyl, lower alkoiiyalkyl, and plfehyl {lower alkyl) 'B is a saturated divalent aliphatic radical. v V

2. 9a. halo A pregame 11B o1 3,20 dione-21- a1 21- diflower-alkyl)acetal. v i 3, 9x 11319 A -pregn'e'ne 3,11,20 trione 21 al 21-di(lower alkyl) acetal. k

4. A steroid selected from the class consisting of those oftlfefoni'mla CH=O and

7. Asia-Bidet the-formula OH and wherein B is a radical of the class consisting of lower alkyl, halo-substituted lower alkyl, loyver'alkoky-alkyl and phenylflower alkyl), and B is a saturated divalent aliphatic radical. Y v 4 8. 9a fluoro A pregnene llfl o1 3,20 dione- 21-al 21-di(-lower alkyl) acetal.

9. 9oz fluoro A pregnen'e 11 3 ol 3,20 dione 21-al 21-dimethyl acetal. I

10. 9a fluoro A iregnene 11,8 61 3,20 dioner 21-211 hydrate.

11. 9a chloro A pregnene 115 ol 3,20 dione- 21-al 2 1-di(lower alkyl) acetal.

12. 9 chloro A pregnene 11p: o1 3,20 dione- 2'1-a1 21-dimethy1 acetal.

13. 9oz chloro A pregnene llfl o1 3,20 dione- 21-al hydrate.

14. 95,113 oxido A pregnene 3,20 dione 21- al 2l-di(lowi' alkyl) acetal.

15. 95,115 oxido A pregnene 3,20 dione 21- a1 21-dimethyl acetal.

References Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES 7 Fried et al.: J. Am. Chem. Soc. 2273-4 (May 19s3) UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,859,212 November 4, 1958 Josef Fried It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 6, line 44, for 913- read 9acolumn 7, line 2, for chlorofrom read ch1oroform-; line 10, for dimethy read dimethy1-; column 8, line 46, for Claisen-Vigreux read C1aisen-Vigneux.

Signed and sealed this 26th day of May 1959.

[SEAL] Attest: KARL H. AXLINE, ROBERT C. WATSON, Attestz'ng Officer. Uonwm'ssioner of Patents. 

1. A STEROID SELECTED FROM THE GROUP CONSISTING OF THOSE OF THE FORMULA
 7. A STEROID OF THE FORMULA 